Ledipasvir/Sofosbuvir Treatment of Hepatitis C Virus is Associated With Reduction in Serum Apolipoprotein Levels

Z.M. Younossi; E. Elsheikh; M. Stepanova; L. Gerber; F. Nader; L.M. Stamm; D.M. Brainard; J.G. McHutchinson


J Viral Hepat. 2015;22(12):977-982. 

In This Article

Abstract and Introduction


The interaction of lipoproteins with hepatitis C virus (HCV) has pathogenic and therapeutic implications. Our aim was to evaluate changes in the apolipoprotein profile of patients with chronic hepatitis C during and after successful cure with ledipasvir and sofosbuvir (LDV/SOF) with and without ribavirin (RBV). One hundred HCV genotype 1 patients who had achieved SVR-12 after treatment with 12 weeks of LDV/SOF ± RBV were selected from the ION-1 clinical trial. Frozen serum samples from baseline, end of treatment and week 4 of follow-up were used to assay apolipoproteins (apoAI, apoAII, apoB, apoCII, apoCIII, apoE) using the Multiplex platform to assess for changes in the apolipoprotein levels. At the end of treatment compared to baseline, a significant reduction in apoAII levels (−14.97 ± 63.44 μg/mL, P = 0.0067) and apoE levels (−4.38 ± 12.19 μg/mL, P < 0.001) was noted. These declines from baseline in apoAII (−16.59 ±66.15 μg/mL, P = 0.0075) and apoE (−2.66 ± 12.64 μg/mL, P = 0.015) persisted at 4 weeks of post-treatment follow-up. In multivariate analysis, treatment with LDV/SOF + RBV was independently associated with reduction in apoE (beta = 5.31 μg/mL, P = 0.002) (compared to RBV-free LDV/SOF) (P < 0.05). In contrast, apoCII levels overall increased from baseline to end of treatment (+2.74 ±11.76 μg/mL, P = 0.03) and persisted at 4 weeks of follow-up (+4.46 ± 12.81 μg/mL from baseline, P = 0.0005). Subgroup analysis revealed an increase in apoCII during treatment only in patients receiving LDV/SOF without RBV (+5.52 ± 11.92 μg/mL, P = 0.0007) but not in patients receiving LDV/SOF + RBV (P = 0.638). Treatment with LDV/SOF ± RBV is associated with a persistent reduction in the apolipoprotein AII and E after achieving cure. These data suggest that treatment with LDV/SOF ± RBV may be associated with alterations in serum apolipoproteins which could potentially impact viral eradication.


Hepatitis C virus (HCV) infection is a major cause of chronic liver disease with an estimated worldwide prevalence of 3% corresponding to at least 170 million infected persons.[1,2] In the United States, HCV infection is the most common aetiologic agent associated with cirrhosis, hepatocellular carcinoma and liver transplantation.[3–5]

Although hepatitis C virus causes a systemic disease with both hepatic and extrahepatic manifestations, it is predominantly a hepatotropic virus targeting the liver. As an organ, liver plays a central role in lipid homoeostasis through production and uptake of lipoproteins. Lipoproteins can be characterized by their densities related to their core lipid (triglycerides and cholesteryl ester) composition. The five main classes according to their density are chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoproteins, low-density lipoprotein (LDL) and high-density lipoproteins (HDL). Lipoproteins can also be characterized by the major apolipoproteins present on their surfaces, some of which are structural (apoB and AI), while others exchange between different lipoprotein particles (apoAII, C and E). Both, apoB[6] and apoE,[7] have been shown to participate in HCV assembly and maturation.

It is postulated that HCV binds to the host lipoproteins LDL and VLDL, and circulates as a lipoviroparticle.[8] The lipoprotein association is thought to facilitate the attachment of HCV to target cells by interacting with the LDL receptor.[9] This interaction may explain the correlation of the increased accumulation of HCV viral RNA in cells with an increased LDL receptor expression.[10,11] Additionally, antibodies directed against LDL receptors inhibit HCV RNA accumulation in cells,[12] and HCV infectivity is neutralized in a dose-dependent manner by antibodies directed against apoB and apoE (major protein components of VLDLs).[7,12] In an in vitro study, binding of HCV core protein to apoAII has also been reported. Additionally, fenofibrate treatment resulted in a parallel increase in apoAII and core protein secretion.[13]

One of the strategies HCV has adopted to escape immune clearance and establish persistent infection is to make use of hepatic lipid pathways. The functional advantage of the association of virions with host lipoproteins has not been completely elucidated, although evidence suggests the utilization of lipoprotein components may both mediate attachment to lipoprotein receptors on the hepatocytes as well as obscuring the circulating viral particles from immunoglobulin recognition, thereby allowing the virus to escape immune surveillance.[14,15]

Molecules targeting the lipoproteins associated with virus particles or the lipoproteins that stimulate virus entry would potentially affect HCV infectivity. Indeed, HCV–lipid interactions may be attractive targets for the development of antiviral drugs, as the targeting of essential host cell factors would limit the development of escape mutations and would directly target the virus components.[16]

In this study, we attempted to evaluate changes in the apolipoprotein profile of patients with chronic hepatitis C (CH-C) during and after successful treatment (SVR-12) with ledipasvir (LDV)/sofosbuvir (SOF) ± ribavirin (RBV).